2. Academic Validation
  3. RYBP promotes HIV-1 latency through promoting H2AK119ub and decreasing H3K4me3

RYBP promotes HIV-1 latency through promoting H2AK119ub and decreasing H3K4me3

  • Cell Commun Signal. 2025 May 13;23(1):222. doi: 10.1186/s12964-025-02221-z.
Xinyi Yang # 1 2,  Yuqi Zhu # 3,  Xiaying Zhao # 3,  Jingna Xun 3 4,  Xingyu Wang 3,  Yipeng Cheng 3,  Su Xiong 3,  Xingwen Yu 3,  Suixiang Li 3,  Danqing Wang 5,  Zhiliang Hu 6,  Yinzhong Shen 4 7,  Shibo Jiang 8,  Hongzhou Lu 9,  Gang Wang 3,  Huanzhang Zhu 10
Affiliations

Affiliations

  • 1 State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute of Fudan University, Fudan University, Shanghai, China. xinyy@fudan.edu.cn.
  • 2 Yunnan Provincial Infectious Diseases Hospital/Yunnan AIDS Care Center, Kunming, China. xinyy@fudan.edu.cn.
  • 3 State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute of Fudan University, Fudan University, Shanghai, China.
  • 4 Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
  • 5 Yunnan Provincial Infectious Diseases Hospital/Yunnan AIDS Care Center, Kunming, China.
  • 6 Department of Infectious Disease, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing Medical University, Center for Global Health, School of Public Health, Nanjing, China.
  • 7 Department of Infectious Diseases and Immunology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
  • 8 Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • 9 Department of Infectious Diseases and Nursing Research Institution, National Clinical Research Center for Infectious Diseases, The Third People's Hospital of Shenzhen, Shenzhen, Guangdong, China.
  • 10 State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Yiwu Research Institute of Fudan University, Fudan University, Shanghai, China. hzzhu@fudan.edu.cn.
  • # Contributed equally.
PMID: 40361117 DOI: 10.1186/s12964-025-02221-z
Abstract

Background: Acquired immunodeficiency syndrome (AIDS) cannot be completely cured, and the main obstacle is the existence of viral reservoirs. However, we currently do not fully understand the molecular mechanisms by which HIV-1 latency is established and maintained.

Methods: Here, based on engineered chromatin immunoprecipitation (enChIP) technology that using FLAG-tagged zinc finger nucleic acid proteins (FLAG-ZFP) that bind to the HIV-1 L region and chromatin immunoprecipitation, we identified RYBP as a new HIV-1 latency-promoting gene. The effect of RYBP on HIV-1 latency was explored in multiple cell lines and primary latency models through gene knockout methods. Western blot and chromatin immunoprecipitation (ChIP) were used to explore the molecular mechanism of RYBP in promoting HIV-1 latency.

Results: Disruption of RYBP gene can activate latent HIV-1 in different latent cell lines and primary latent cell models. Mechanistically, the HIV-1 long terminal repeats (LTR) region binding protein Yin Yang 1 (YY1) can recruit RYBP to the HIV-1 L region. Then, RYBP can further recruit KDM2B, thereby promoting the increased ubiquitination level of H2AK119 and decreases the level of H3K4me3, to decrease HIV-1 L transcriptional elongation and enter a latent state. At the same time, during the stage of viral transcription and replication, Tat protein can inhibit the expression of RYBP, promoting viral transcription and replication. Finally, we found that the H2AK119ub inhibitor PRT4165 can promote latent HIV-1 activation and has good synergy with reported latent reactivating agents.

Conclusion: These results provide mechanistically new insights into a critical role of RYBP in the regulation of histone modification and H2AK119ub may be directly targeted to control HIV reservoirs.

Keywords

EnChIP; H2AK119ub; HIV-1 latency; KDM2B; RYBP.

Figures
Products